Patent Application
20180008575
Binge eating disorder (BED) is characterized by binge eating without purging, and is often, but not necessarily, associated with obesity. BED is challenging to treat and carries significant medical and psychological risks.
BED is associated with significant morbidity, including medical complications related to obesity (e.g., type 2 diabetes, cardiovascular disease, hypertension, stroke), eating disorder psychopathology (e.g., weight and shape concerns), psychiatric co-morbidity, reduced quality of life, and impaired social functioning. Psychiatric comorbidities that may occur with BED include depression, bipolar disorder, anxiety disorders, substance abuse disorders, and attention-deficit/hyperactivity disorder (ADHD).
Analysis of psychological and pharmacological treatments for BED found that psychotherapy and structured self-help treatments had more robust effects on outcomes, including binge abstinence. However, while specialized psychotherapies, such as cognitive behavior therapy and interpersonal therapy, and self-help strategies are effective for reducing binge eating, not all patients respond adequately and these treatments are generally not effective for the obesity associated with BED.
Further, some pharmacological treatments may cause a worsening of symptoms. For instance, antidepressants may cause a worsening of depression and weight gain. Meta-analysis of some placebo-controlled studies of antidepressants in patients with BED show significantly higher binge eating remission rates for the antidepressant group compared with the placebo group and no differences are found in the mean frequency of binge eating episodes at the end of treatment, in BMI, or in treatment discontinuation for any reason.
Accordingly, there exists a need for new treatments for BED.
Provided is a method of treating binge eating disorder (BED) in a patient in need thereof comprising administering a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to the patient.
Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments, are intended for purposes of illustration only and are not intended to limit the scope of this disclosure.
As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is shown as Formula I below.
“(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” and “(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” are used interchangeably herein.
(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is an unbalanced triple reuptake inhibitor with the most potency towards norepinephrine reuptake (NE), one-sixth as much towards dopamine reuptake (DA), and one-fourteenth as much towards serotonin reuptake (5-HT).
While stimulants have been used in individuals with binge eating, such treatment may not be optimal because stimulants may result in increased anxiety and come with a risk of abuse, dependency, and diversion. The risk of increased anxiety and abuse and dependency for stimulants may be especially concerning with this patient population as anxiety disorders and substance abuse disorders are often comorbid with BED.
However, a drug with minimal to no effect on dopamine may not provide optimal treatment for binge eating disorder either.
(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane enhances dopamine function, but without the pronounced dopaminergic activities of stimulants. Thus, in individuals with BED, the unbalanced norepinephrine-dopamine-serotonin reuptake inhibition profile of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may affect the norepinephrine, dopamine, and serotonin circuitries without causing increased anxiety and irritability and without triggering substance abuse that may be seen with stimulants.
In addition, the multi-functional effects of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be useful in treating BED as well as comorbidities, such as depression, bipolar disorder, anxiety disorders, substance abuse disorders, personality disorder, somatoform disorder, and attention-deficit/hyperactivity disorder.
Further, affecting the norepinephrine, dopamine, and serotonin circuitries with one drug may avoid pharmacologic drug-drug interactions (DDIs). For instance, administering two drugs with different effects on the norepinephrine, dopamine, and/or serotonin circuitries may result in off-target interactions potentially leading to undesirable and unexpected norepinephrine, dopamine, and/or serotonin levels.
It has been reported that cytochrome P450 enzyme isoforms (CYPs), which catalyze oxidative reactions, account for the metabolism of 75% of all drugs, and in particular, about 80% of drugs cleared by CYPs are metabolized by four CYP isoforms—CYP3A4, CYP2D6, CYP2C9 and CYP2C19. Thus, these four CYPs are potential candidates for DDIs. Physicians consider potential DDIs and metabolic pathway(s) when selecting treatments. (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is primarily metabolized by monoamine oxidase A (MAO A), which may spare the liver and may reduce drug-drug interactions if (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is used in a combination therapy, e.g., with a drug that is metabolized by CYPs.
(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be synthesized as described in U.S. Pat. No. 8,461,196, U.S. Patent Publication No. 2014/0206740, or International Publication No. WO 2013/019271, each of which are incorporated herein by reference in their entirety.
As used herein, “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” embraces the compound in any form, for example, free or pharmaceutically acceptable salt form, e.g., as a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable salts are known in the art and include salts that are physiologically acceptable at the dosage amount and form to be administered, for example, hydrochloride salts.
As used herein, “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” is also to be understood as embracing the compound in crystalline and amorphous form including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” may be used interchangeably herein, and are meant to include all crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), and conformational polymorphs, as well as mixtures thereof, unless a particular crystalline form is referred to.
Crystalline and amorphous forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be used in any combination or in forms that are substantially free of one or more of the other crystalline forms or free of the amorphous form.
As used herein, “substantially free of other polymorphic forms” means that the crystalline material contains no more than 10% w/w of any other crystalline form, e.g., no more than 5% w/w of any other crystalline form, e.g., no more than 2% w/w of any other crystalline form, e.g., no more than 1% w/w of any other crystalline form.
(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may in some cases also exist in prodrug form. Prodrugs are considered to be any covalently bonded carriers that release the active parent drug in vivo.
As used herein, the term “patient” includes human or non-human (i.e., animal) patient. In some embodiments, patient encompasses both human and nonhuman. In some embodiments, patient means a nonhuman. In other embodiments, patient means a human.
As used herein, “concurrently” means the compounds are administered simultaneously or within the same composition. In some embodiments, the compounds are administered simultaneously. In some embodiments, the compounds are administered within the same composition.
Anxiety may be characterized by feelings of tension and worried thoughts. Anxiety disorders may cause recurring intrusive thoughts or concerns. As used herein, “anxiety disorder” includes generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder.
As used herein, “substance abuse disorder” includes alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-use disorders, inhalant-related disorders, and opioid-related disorders. For instance, “substance abuse disorder” includes alcohol abuse, nicotine abuse, opioid abuse, and stimulant (like cocaine and methamphetamine) abuse.
As used herein, “somatoform disorder” includes somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, and somatoform disorder not otherwise specified (NOS).
As used herein, “therapeutically effective amount” refers to an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit, such as amelioration of symptoms or elimination of the disease. The specific dose of substance administered to obtain a therapeutic benefit will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific substance administered, the route of administration, the condition being treated, and the individual being treated.
As used herein, “treatment” and “treating” encompass amelioration of symptoms or elimination of binge eating disorder, as well as treatment of the cause of binge eating disorder. For example, “treatment” and “treating” encompass suppression or improvement of the symptoms of binge eating disorder.
Binge eating disorder involves recurrent episodes of binge eating. A binge-eating episode may encompass eating, in a discrete period of time (e.g., within any 2-hour period), an amount of food that is larger than most people would eat during a similar period of time and under similar circumstances and a sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating). A binge-eating episode may also encompass three (or more) of the following: eating much more rapidly than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of being embarrassed by how much one is eating, and feeling disgusted with oneself, depressed, or very guilty after overeating. Binge eating disorder may also encompass marked distress regarding binge eating. Binge eating may occur, on average, at least once a week for three months. Binge eating is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging).
Provided is a method (Method 1) of treating binge eating disorder in a patient in need thereof comprising administering a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to the patient.
Further provided is a method (Method 2) of treating comorbid binge eating disorder and another psychiatric disorder in a patient in need thereof comprising administering a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to the patient, e.g., further provided is
Further provided is a method (Method 3) of treating comorbid binge eating disorder and obesity in a patient in need thereof comprising administering a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to the patient.
Further provided is a method (Method 4) of treating comorbid binge eating disorder and fibromyalgia in a patient in need thereof comprising administering a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to the patient.
Further provided is any of Method 1, 2, 3, or 4, e.g., Method 1, e.g., Method 2 (e.g., any of Method 2i, Method 2ii, Method 2iii, Method 2iv, Method 2v, Method 2vi, or Method 2vii), e.g., Method 3, e.g., Method 4, as follows:
Also provided is use of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treating binge eating disorder, e.g., for use in any of Method 1 or 1.1-1.19.
Also provided is use of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treating comorbid binge eating disorder and another psychiatric disorder, e.g., for use in any of Method 2 (e.g., any of Method 2i, Method 2ii, Method 2iii, Method 2iv, Method 2v, Method 2vi, or Method 2vii) or 1.1-1.19.
Also provided is use of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treating comorbid binge eating disorder and obesity, e.g., for use in any of Method 3 or 1.1-1.19.
Also provided is use of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treating comorbid binge eating disorder and fibromyalgia, e.g., for use in any of Method 4 or 1.1-1.19.
Also provided is a pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier for use in treating binge eating disorder, e.g., for use in any of Method 1 or 1.1-1.19.
Also provided is a pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier for use in treating comorbid binge eating disorder and another psychiatric disorder, e.g., for use in any of Method 2 (e.g., any of Method 2i, Method 2ii, Method 2iii, Method 2iv, Method 2v, Method 2vi, or Method 2vii) or 1.1-1.19.
Also provided is a pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier for use in treating comorbid binge eating disorder and obesity, e.g., for use in any of Method 3 or 1.1-1.19.
Also provided is a pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier for use in treating comorbid binge eating disorder and fibromyalgia, e.g., for use in any of Method 4 or 1.1-1.19.
A dose or method of administration of the dose of the present disclosure is not particularly limited. Dosages employed in practicing the present disclosure will of course vary depending, e.g. on the mode of administration and the therapy desired. In general, satisfactory results, e.g. for the treatment of BED are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. An indicated daily dosage for oral administration may be in the range of from about 0.75 mg to 200 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 mg to 75 mg or 150 mg, e.g. from about 0.2 mg or 2.0 mg or 50 mg or 75 mg or 100 mg to 200 mg or 500 mg of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, together with a pharmaceutically acceptable diluent or carrier therefor.
(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, including by sustained release, although various other known delivery routes, devices and methods can likewise be employed. In some embodiments, (1R,5 S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is administered in a sustained release pharmaceutical composition, e.g., an oral sustained release pharmaceutical composition, comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, which provides therapeutically effective levels of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane over a sustained delivery period of approximately 6 hours or longer, e.g., 8 hours or longer, e.g., 12 hours or longer, e.g., 18 hours or longer, e.g., 24 hours or longer. In some embodiments, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is administered in an immediate release pharmaceutical composition, e.g., an oral immediate release pharmaceutical composition, comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.
Pharmaceutical compositions comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.
Where two active agents are administered, the therapeutically effective amount of each agent may be below the amount needed for activity as monotherapy. Accordingly, a subthreshold amount (i.e., an amount below the level necessary for efficacy as monotherapy) may be considered therapeutically effective. Indeed, an advantage of administering different agents with different mechanisms of action and different side effect profiles may be to reduce the dosage and side effects of either or both agents, as well as to enhance or potentiate their activity as monotherapy.
This application claims priority to U.S. Provisional Application No. 62/360,956 filed Jul. 11, 2016, the contents of which are hereby incorporated by reference in entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62360956 | Jul 2016 | US |
